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Small vessel diseases in a mechanistic perspective: Targets for Intervention Affected pathways and mechanistic exploitation for prevention of stroke and dementia

Periodic Reporting for period 2 - SVDs-at-target (Small vessel diseases in a mechanistic perspective: Targets for InterventionAffected pathways and mechanistic exploitation for prevention of stroke and dementia)

Reporting period: 2017-07-01 to 2018-12-31

Cerebral small vessel disease (SVD) covers a variety of changes in the small arterioles and venules in the brain. It gives rise to one in five strokes worldwide and constitutes a major source of cognitive decline and disability in the elderly. Despite this profound impact on human health, the disease process and the key biological mechanisms remain largely unknown and there are no treatments with proven efficacy against SVDs. This network brings together basic scientists and academic clinicians and will make use of novel animal models and expertly phenotyped patient cohorts to elucidate the main risk factors of SVDs: blood pressure variability, leakage of the blood brain barrier, the role of the extracellular matrix and activation of inflammation.
The main objectives are to:
– define common molecular, cellular, and physiological mechanisms underlying the regulation of blood flow, and barrier and clearance functions of microvessels that are compromised in different SVDs.
– determine how these common mechanistic defects intersect to drive brain parenchymal damage, which lead to stroke and dementia as the major comorbidities.
– validate the relevance of mechanisms and biomarkers through interventions.
In the second period, we made substantial progress towards all work packages:

Blood Pressure variability and microvascular dysfunction
We have demonstrated in animal models the impairment of functional hyperemia as a common pathological phenomenon in both monogenic and sporadic forms of SVDs. Furthermore, we have identified several key molecules such as capillary Kir channel and PIP2 as the cause of these deficits, which has a great potential as therapeutic targets for the treatment of SVDs.
Using cohort and trial data we could show that recent premorbid blood pressure control is strongly temporarily related to acute lacunar events at younger ages, suggesting a direct role of blood pressure in accelerating causal pathology and highlighting the need to control hypertension quickly. Common carotid and internal carotid artery pulsatility index are associated with global SVD burden, especially in individuals aged<70 and may be causally related. In stroke and TIA patients, visit-to-visit and day-to-day BP-variability predicts increased risks of recurrent stroke and cardiovascular events, independent of mean blood pressure. Although residual nocturnal hypertension is more common than residual daytime hypertension, it was not a major risk factor for stroke or cardiovascular events.

Blood brain barrier (BBB) and perivascular flow
The effect of BBB malfunction on the perivascular space and CSF fluxes was examined in rodent models. Our analysis indicate that acute arterial hypertension changes vessel wall dynamics leading to a significant suppression of perivascular influx as well as a delay in clearance of CSF tracers from the brain parenchyma.
The multicentre clinical study INVESTIGATE-SVDs uses MRI brain scans to assess microvascular function by measuring BBB permeability, CVR, and cerebral pulsatility. All regulatory approvals in three European countries have been obtained, MR protocols were harmonised across all study sites, novel software and operating procedures were developed to analyse imaging data. With the inclusion of the 48th patients out of 75 patients, we passed mid-term recruitment.

Microvascular matrisome
Collection of tissues from five distinct mouse models of SVD has been completed and a novel approach has been developed and validated to quantify microvascular matrisome changes in murine brain vessels. With this approach, we could identify matrisome proteins differentially expressed in SVDs. Our data revealed major changes in the microvascular matrisome associated with aging, which is consistent with aging as the major risk factor of SVD.
The multicentre clinical study ZOOM@SVDs aims to establish novel markers of microvascular dysfunction in patients with SVD. All ethical approvals in the Netherlands and Germany have been granted.. Meanwhile recruitment is nearly finished. In parallel, the MRI methods were refined and an analysis pipeline for pulsatility measurements was developed.

Inflammatory mechanisms
We have investigated four mouse models of SVDs at different ages using immunofluorescence confocal microscopy for immune cells and their location in the neurovascular unit. Our data show that infiltrating immune cells are not present in the different SVD models, suggesting that they do not contribute to SVD pathogenesis. However, altered resident immune cells, namely microglia, were found in several brain regions of the SVD mice suggesting that changes in the activation state of resident microglia may play a role pathogenesis of hypertension related SVDs.
To relate immune cell characterization to post-mortem brain specimens of SVD patients we procured brain samples of sporadic cSVDs patients and controls from the Edinburgh brain bank. We will examine these specimens for immune cells, BBB dysfunction, matrisome and their association with white matter damage using immunohistochemistry. Circulating immune cells will be characterized in blood samples of patients from our clinical studies using flow cytometry. As of
The ambition of SVDs@target is to identify key mechanisms common to multiple SVDs and to validate novel mechanisms through intervention. Our approach – studying multiple SVDs in parallel and linking this with interventions for validation in animals and humans – is novel and devised to accelerate transfer to clinic. Our preliminary results already provide a better understanding of disease pathways leading from basic risk factors (genetics, environmental risk factors, vascular risk factors including hypertension) to functional deficits in small brain vessels, parenchymal brain lesions, and eventually key clinical manifestations of cerebral SVD, i.e. stroke and dementia – one of the most pressing health issues in the EU. They further provide new directions for clinical research, such as on the role of early life risk factors for stroke and dementia and the role of blood pressure variability for stroke and dementia risk.
SVDs@target: Scientific concept and approach taken by SVDs@target